Pomegranate (Punica granatum) fruits have been used for centuries in folk medicine. They are consumed fresh and as juice, both of which are excellent sources of ellagitannins and ellagic acid. Ellagitannins (ETs) are polymeric polyphenols abundant in some fruits and nuts such as pomegranates, raspberries, strawberries, black raspberries, walnuts and almonds. Despite numerous reports of the biological properties and human health benefits of ETs, knowledge of their bioavailability, pharmacokinetics, disposition and metabolic fate in humans is limited. Commercially-produced pomegranate juice contains gallagyl-type ellagitannins, including punicalagin isomers (1500-1900 mg/L), undefined hydrolyzable tannins (400-500 mg/L), and ellagic acid and its glycosides (120-260 mg/L). Gil et al. J. Agric. Food Chem. 2000, 48, 4581-4589. Punicalagins, ellagitannins in which gallagic and ellagic acids are linked to a glucose molecule, are abundant in pomegranate peel. Punicalagin isomers and ellagic acid derivatives are not present in the aril juice, but during industrial juice processing they are extracted from the husk and membrane surrounding the arils and released in large quantities into the juice. The fruit arils of pomegranates contain other polyphenols, such as anthocyanins, responsible for the fruit's bright ruby-red color. Ellagitannins belong to a group of compounds known as hydrolyzable tannins, which release ellagic acid (EA) upon hydrolysis.
Unfortunately, ellagitannins are typically poorly absorbed by the human gut. However, a number of metabolites derived from ellagitannins are absorbed by the human gut, including certain metabolites ultimately formed in the gut by commensal microorganisms (i.e., intestinal microflora). Ellagitannins release ellagic acid under physiological conditions in vivo, and ellagic acid is then gradually metabolized by the gut microflora in the intestine to produce the urolithins. Once the metabolites are absorbed, they are further metabolized to produce urolithin glucuronides and/or sulfates. There is growing evidence that urolithins have potent antioxidant, anticancer, and anti-hyperproliferative activity. See US 2011/0065662; US 2012/0164243; and US 2014/0018415; all of which are incorporated by reference.
Although urolithins are derived from ETs present in certain foods (e.g., pomegranates), the consumption of these foods does not always lead to sufficient bioavailability of the therapeutic metabolites. Specifically, certain individuals, referred to herein as non-producers, fail to produce detectable amounts of the metabolites after consumption of ET-containing foods (e.g., pomegranate juice). Even among individuals who are producers, there is a great deal of variation (from very low to very high) in the amount of urolithin metabolites produced. Furthermore, any FDA-approved therapeutic use of urolithins would require a reliable and standard dosing regimen; that is, a known dose of a fully-characterized compound or compounds. It would thus be necessary to administer one or more selected urolithins directly to patients in need thereof.
In light of the therapeutic promise of urolithin compounds, a tremendous need exists for a safe, economical, reliable, and scalable synthesis approach to the urolithins. A reliable source of multi-kilo and commercial quantities of urolithin compounds will allow their further clinical development, with the ultimate goal of exploiting their full therapeutic potential.